Old vaccines may be better than new

Mutations could make recent tuberculosis vaccines less powerful than older ones.

Genetic changes in a commonly used vaccine for tuberculosis could be contributing to its spotty performance, new research
suggests.

The results come as researchers race to develop a new and improved vaccine to defend against the burgeoning worldwide epidemic
of tuberculosis. The current vaccine — called the Bacillus Calmette-Guerin (BCG) vaccine — has been used since the early 1900s
and prevents tuberculosis in most children, but provides inconsistent protection in adults.

The BCG vaccine consists of several strains. They all come from the same source, but were grown in different labs. Stewart
Cole of the Pasteur Institute in Paris, France hypothesized that genetic differences acquired during this growth could account
for some of the variation in vaccine performance.

To assess this, Cole and his colleagues compared the genomes of ten strains of the BCG vaccine. Their results, published this
week in Proceedings of the National Academy of Sciences of the USA, reveal that BCG strains differ in both genomic composition and in gene expression — one vaccine called BCG Pasteur, for
example, was lacking 133 genes found in a more recent isolate.1 The researchers then used this genetic information to build a rough family tree of the various strains. They conclude that
the older, less commonly used strains — such as BCG Japan — should be genetically closest to the source material for the vaccine,
and so should produce more antigenic proteins.

Cole notes that at least one clinical trial has shown that BCG Japan triggers a stronger immune response in newborns than
a newer one called BCG Danish.

Cole says that clinicians should be using BCG Japan whenever possible, and that researchers should use this strain to develop
new vaccines. "With increasing levels of drug-resistant tuberculosis, we could certainly use a better vaccine now," says Cole.
"There's a burning need for it."

But Marcus Horwitz, an immunologist at the University of California, Los Angeles, says that more animal and clinical studies
are needed before researchers throw their support behind BCG Japan. "Based on the current literature, I think it's unlikely
that strain differences would have a major impact on efficacy," says Horwitz. Some meta-analyses of tuberculosis vaccinations
have shown no difference in the efficacy between BCG strains, he says.

Grown on potatoes

The probable culprit behind the genetic differences is the method used to store the vaccine immediately after it is developed
from Mycobacterium bovis, an isolate of the tuberculosis bacterium that infects cattle. A hundred years ago, researchers couldn't freeze-dry their
vaccines, they had to keep them alive. Researchers grew the bacterium in the laboratory on potato slices coated with glycerol,
and transferred them to new cultures before they became too dense and unhealthy in a process called "passaging".

Life on a potato slice is a far cry from life in a cow. This could have favoured a different genetic composition and, over
time, genes that were no longer needed might have been lost or expressed at lower levels.

Since the 1960s, vaccines have been archived in frozen stocks, and no preparation of vaccine is passaged more than 12 times.
But the BCG vaccine had been distributed to different labs well before then, giving rise to different strains that have each
had plenty of opportunities to mutate. Even the relatively recent BCG Pasteur strain, for example, has been passaged 1,173
times.

Selective strain

The idea that strain differences are contributing to the variation in vaccine efficacy is not new to the field. Some researchers
have raised the possibility that clinicians might have favoured vaccines that produced less scarring, and this may have led
to the inadvertent selection of less reactive strains.

But strain differences cannot account for all of the frustrating variations in BCG efficacy, cautions immunologist Hazel Dockrell
of the London School of Hygiene & Tropical Medicine in the United Kingdom, because the same strain can have differing degrees
of protection when used in different places.

Horwitz adds that Cole's study is an important illustration of how vaccines can change over time. Even modern manufacturing
techniques can prompt genetic changes in vaccines, and that's something that Horwitz's lab has been keeping in mind as they
work to develop a new tuberculosis vaccine, he says.

"I bet in the future we'll be doing a battery of genetic tests to ensure the vaccines are what we think," says Horwitz. "If
too many changes take place between the time you complete your human trial and when you distribute the vaccine, you have to
worry."